The present invention relates generally to stents for implantation in a body to maintain the lumen of a duct or vessel open for unimpeded passage of liquid, solid or gas therethrough. For example, stents are typically implanted to prevent collapse or to impede narrowing of a blood vessel such as a coronary artery, so that blood will continue to flow freely through the vessel after an occlusion has been found and/or an angioplasty procedure has been performed, but stents may also be implanted in other body ducts for a similar purpose of allowing other body fluids or solid material to pass through the duct. More particularly, the present invention is directed to stents which are rendered radioactive prior to implantation to inhibit the formation or reformation of a stenotic region or to reduce the rate of growth of a tumor that otherwise would occlude a duct.
The benefits of angioplasty, particularly percutaneous transluminal coronary angioplasty (PTCA) and most especially balloon angioplasty, has been amply demonstrated over more than a decade. Angioplasty is an effective procedure to open blood vessels which have been partly or even fully occluded by a stenotic region such as a buildup of plaque or fatty deposits on the inner lining. Left untreated, such deposits in the coronary arteries could result in myocardial infarction and death. Blockage occurring in other blood vessels may lead to maladies such as phlebitis, paralysis or atrophy, for example.
With PTCA patients, however, it was found that restenosis occurs in as much as 50% of the cases, typically within only a few weeks or months following the initial procedure. A repeat procedure in such cases often demonstrated little or no effect. It was discovered that the restenosis was usually attributable not to new deposits of plaque or to thrombus formation, but rather to a response of the tissue to trauma that resulted from the angioplasty procedure itself, even the rather mild trauma induced by balloon angioplasty in contrast to laser or scraping techniques. Contact with the inner lining of the vessel wall induces a form of cellular hyperplasia manifested by a profound proliferation of the smooth muscle cells, to an extent that reocclusion may even exceed the clogging that prompted resort to the original angioplasty procedure. Production of the new tissue cells occurs within the intimal and medial layers, in a mechanism analogous to wound healing and scar tissue.
To reduce the likelihood of reocclusion of the vessel, it has become common practice for the physician to implant a stent in the patient at the site of the angioplasty or atherectomy procedure, immediately following that procedure, as a prophylactic measure. The stent is advanced on a balloon catheter to the designated site of the prior (or even contemporaneous) procedure under fluoroscopic observation. When the stent is positioned at the proper site, the balloon is inflated to expand the stent radially to an inner diameter at or slightly larger than the normal unobstructed inner diameter of the arterial wall, for permanent retention at the site. The stent implant procedure from the time of initial insertion to the time of retracting the balloon is relatively brief, and certainly far less invasive than coronary bypass surgery.
Despite its considerable benefits, coronary stenting alone is not a panacea, as studies have shown that about 30% of the patient population subjected to that procedure will still experience restenosis. Clearly, that percentage is still quite favorable compared to the approximate 50% recurrence rate for patients who have had a PTCA procedure without stent insertion at the angioplasty site. But improvement is needed. Also, risks of inflammation of the vessel wall and of attachment of thrombi at the site are exacerbated by the very presence of the stent in the vessel.
A stent is typically composed of a biologically compatible material (biomaterial) such as a biocompatible metal wire mesh of tubular shape or a metallic tube populated with sidewall through-holes to permit radial expansion thereof The stent should be of sufficient strength and rigidity to maintain its shape after deployment, and to resist the normal elastic recoil of the artery that occurs after the vessel wall has been stretched. After the stent is inserted into the vessel, its presence in the blood stream may induce a local or even systemic activation of the patient's hemostase coagulation system. When stents are used in blood vessels of less than about 3 millimeters (mm) diameter, such as the coronary arteries, the incidence of complications increases to an even greater extent.
In the past several years, considerable research has been devoted worldwide to studying the mechanisms of restenosis. Research conducted by the applicant has indicated that local thrombus formation is one of the mechanisms that promote restenosis. Animal research by the applicant has shown that a further 30% reduction in the restenosis rate (i.e., the rate of recurrence) may be achieved if the stent is coated with a biocompatible, non-foreign body-inducing, biodegradable polylactic acid of thin paint-like thickness in a range below 100 microns, and preferably about 10 microns thick. This thin coating on a metallic stent may be used to release drugs incorporated therein, such as hirudin and/or a platelet inhibitor such as prostacyclin (PGI.sub.2), a prostaglandin. Both of these drugs are effective to inhibit proliferation of smooth muscle cells, and decrease the activation of the intrinsic and extrinsic coagulation system. Therefore, the potential for a very significant reduction in restenosis has been demonstrated in these animal experiments.
That invention is disclosed in co-pending patent application Ser. No. 08/798,333, now U.S. Pat. No. 5,788,979, of the applicant herein. The stent is coated with a biodegradable substance or composition which undergoes continuous degradation in the presence of body fluids such as blood, to self-cleanse the surface as well as to release thrombus inhibitors incorporated in the coating. Disintegration of the carrier occurs slowly through hydrolytic, enzymatic or other degenerative processes. The biodegradable coating acts to prevent the adhesion of thrombi to the biomaterial or the coating surface, especially as a result of the inhibitors in the coating, which undergo slow release with the controlled degradation of the carrier. Blood components such as albumin, adhesive proteins, and thrombocytes can adhere to the surface of the biomaterial, if at all, for only very limited time because of the continuous cleansing action along the entire surface that results from the ongoing biodegradation.
Materials used for the biodegradable coating and the slow, continuous release of drugs incorporated therein include synthetic and naturally occurring aliphatic and hydroxy polymers of lactic acid, glycolic acid, mixed polymers and blends. Alternative materials for those purposes include biodegradable synthetic polymers such as polyhydroxybutyrates, polyhydroxyvaleriates and blends, and polydioxanon, modified starch, gelatine, modified cellulose, caprolactaine polymers, acrylic acid and methacrylic acid and their derivatives. It is important that the coating have tight adhesion to the surface of the biomaterial, which can be accomplished by applying the aforementioned thin, paint-like coating of the biodegradable material that may have coagulation inhibitors blended therein, as by dipping or spraying, followed by drying, before implanting the coated biomaterial device.
Two or more different drugs suitable for inhibiting coagulation may be incorporated into the carrier to provide a synergistic effect with release as the coating slowly disintegrates, as where one substance inhibits plasmatic coagulation and another inhibits platelet-induced, cellular coagulation. Hyperplasia is inhibited or suppressed as well, and infection is avoided even when the coating is applied to the biomaterial under non-aseptic conditions.
Hirudin is a naturally occurring and potent thrombin inhibitor that may be incorporated into the carrier with very beneficial results. Similar results are achievable with natural or synthetic prostaglandin derivative instead of or in addition to the hirudin. Specific platelet inhibitors that act on the GP IIb/IIIa receptor are especially helpful in preventing platelet activation following coronary interventions. Anti-adhesive peptides are also suitable, especially with thrombocyte aggregation inhibitors. Inhibition of adhesive proteins which function as bridging proteins tends to preclude adhesion and aggregation of thrombocytes. Locally effective, naturally occurring fibrinolytic substance such as Urokinase, r-TPA or Streptokinase, when added to the coating carrier for slow release, enhance continuous selfcleaning of the surface.
Anti-proliferation substances may be incorporated into the coating carrier to slow proliferation of smooth muscle cells at the internal surface of the vascular wall. Such substances include corticoids and dexamethasone, which prevent local inflammation and further inducement of clotting by mediators of inflammation. Substances such as taxol, tamoxifen and other cytostatic drugs directly interfere with intimal and medial hyperplasia, to slow or prevent restenosis, especially when incorporated into the coating carrier for slow release during biodegradation. Local relaxation of a vessel can be achieved by inclusion of nitrogen monoxide (NO) or other drugs that release NO, such as organic nitrates or molsidomin, or SIN1, its biologically effective metabolite.
A slow release of appropriate drugs incorporated in the biodegradable coating can serve to prevent thrombus formation and also to inhibit inflammatory responses and restenosis of a coronary artery in which a stent is implanted. In this respect, another factor that contributes to restenosis is the natural elastic recoil of the artery and resulting loss of lumen diameter that follows an angioplasty procedure. Stenting serves to stabilize the artery and to resist this natural recoil, by virtue of the rigid structure of the metal stent in its expanded state.
The amount and dosage of the drug or combination of drugs incorporated into and released from the biodegradable carrier material is adjusted to produce a local suppression of the thrombotic and restenotic processes, while allowing systemic clotting of the blood. The active period of the coated stent may be adjusted by varying the thickness of the coating, the specific type of biodegradable material selected for the carrier, and the specific time release of incorporated drugs or other substances selected to prevent thrombus formation or attachment, subsequent restenosis and inflammation of the vessel.
The biodegradable coating undergoes virtually complete disintegration during an initial period of from two weeks to about three months following implantation of the stent. By that time the mechanisms that promote restenosis will have subsided, and a natural tissue layer of limited extent will have begun to form on the stent. This acute response is deemed to be most important, substantially lessening a need for more long-term action. In a study conducted by the applicant, fully four weeks after implantation of a coated stent in a coronary artery of a sheep the device was found to be unobstructed and to have kept the artery fully open for blood flow therethrough, whereas an uncoated stent implanted at the same time displayed a considerably reduced lumen diameter.
The biodegradable coating may also be applied to the stent in multiple layers, either to achieve a desired thickness of the overall coating or a portion thereof for prolonged action, or to employ a different beneficial substance or substances in each layer to provide a desired response during a particular period following implantation of the coated stent. For example, at the moment the stent is introduced into the vessel, thrombus formation will commence, so that a need exists for a top layer if not the entire layer of the coating to be most effective against this early thrombus formation, with a relatively rapid release of the incorporated, potent anticoagulation drug to complement the self-cleansing action of the disintegrating carrier. For the longer term of two weeks to three months after implantation, greater concern resides in the possibility of intimal hyperplasia that can again narrow or fully obstruct the lumen of the vessel. Hence, the same substance as was present or a different substance from that in the top layer might be selected for use in the application of the coating to meet such exigencies. Hirudin, for example, can be effective against both of these mechanisms or phenomena.
The prior art has suggested the use of radiation to inhibit restenosis. Fischell et al. proposes in U.S. Pat. No. 4,768,507 the use of a special percutaneous insertion catheter for purposes of enhancing luminal dilatation, preventing arterial restenosis, and preventing vessel blockage resulting from intimal dissection following balloon and other methods of angioplasty.
In U.S. Pat. No. 4,779,641 and co-pending European patent application No. 92309580.6, the use of an interbiliary duct stent is disclosed. There, radioactive coils of a wire which are embedded into the interior wall of the bile duct ostensibly to prevent restenotic processes from occurring.
U.S. Pat. No. 4,448,691 and co-pending European patent application No. 90313433.6 disclose a helical wire stent, provided for insertion into an artery following balloon angioplasty or atherectomy, which incorporates or is plated with a radioisotope. According to that patent, a radioactive stent will decrease the proliferation of smooth muscle cells. The disclosure teaches that the stent may be made radioactive by irradiation or by incorporating a radioisotope into the material of which the stent is composed. Another solution would be to locate the radioisotope at the core of the tubular stent or to plate the radioisotope onto the surface of the stent. The patent also teaches, aside from the provision of radioactivity of the stent, that an outer coating of anti-thrombogenic material might be applied to the stent.
U.S. Pat. No. 5,059,166 to Fischell et al. discloses a helical coil spring stent composed of a pure metal which is made radioactive by irradiation. Alternative embodiments disclosed in summary fashion in the patent include a steel helical stent which is alloyed with a metal that can be made radioactive, such as phosphorus (14.3 day half life); or a helical coil which has a radioisotope core and a spring material covering over the core; or a coil spring core plated with a radioisotope such as gold 198 (Au.sup.198, which has a half life of 2.7days), which may be coated with an anti-thrombogenic layer of carbon.
Clinical basic science reports such as "Inhibition of neointimal proliferation with low dose irradiation from a beta particle emitting stent" by John Laird et al published in Circulation (93:529-536, 1996) describe creating a beta particle-emitting stent by bombarding the outside of a titanium wire with phosphorus. The implantation of phosphorus into the titanium wire was achieved by placing the P.sup.31 into a special vacuum apparatus, and then vaporizing, ionizing and, accelerating the ions with a higher voltage so that the P.sup.31 atoms become buried beneath the surface of the titanium wire in a thickness of about 1/3 micron. After exposing the wire together with the phosphorus radioisotope for several hours to a flux of slow neutrons part of the P.sup.31 atoms were converted into a P.sup.32, a pure beta particle emitter with a maximum energy of 1.709 megaelectron-volts, an average of 0.695 megaelectron-volts, and a half-life of 14.6 days.
Despite the convincing clinical results obtained by this method, practical application of the method in human patients raises considerable concerns. First, it is difficult to create a pure beta emitter from phosphorus if a stent is exposed to a flux of slow neutrons. In addition to converting phosphorus from P.sup.31 to P.sup.32, the metallic structure of the titanium wire will become radioactive. Therefore, about 20 days are needed to allow the radiation to decay, especially gamma radiation which originates from the titanium wire. Even worse is the situation where a metal such as stainless steel undergoes radioactive irradiation, resulting in production of unwanted .gamma. radiation and a wide range of short and long term radionuclei such as cobalt.sup.57, iron.sup.55, zinc.sup.65, molybdenum.sup.99, cobalt.sup.55. A pure beta radiation emitter with a penetration depth of about 3 millimeters is clearly superior for a radioactive stent for purposes of local action, side effects, and handling.
Reports have indicated that good results have been obtained with a radioactive wire inserted into the coronary arteries or into arteriosclerotic vessels of animals. Results obtained with a gamma radiation source from a wire stems from the deeper penetration of gamma radiation, which is about 10 mm. Assuming that the vessel is 3 to 4 mm in diameter, a distance of 2 to 4 mm depending on the actual placement of the wire toward a side wall has to be overcome before the radiation acts. Therefore, the clinical results that have been obtained with radioactive guide wires that have been inserted into the coronary arteries for a period ranging from about 4 to 20 minutes for delivery of a total dosage of about 8 to 18 Gray (Gy) have shown that gamma radiation has a beneficial effect while beta radiation from a wire is less favorable. On the other hand, gamma radiation which originates from a stainless steel stent such as composed of 316L is less favorable since the properties of .beta. radiation such as a short half-life and a short penetration depth are superior to .gamma. radiation originating from radioactive 316L with a long half-life and a deeper penetration since the proliferative processes of smooth muscle cell proliferation occur within the first 20 to 30 days and only in the very close vicinity of the stent.
In addition, a half-life which is too short such as one to two days considerably impacts on logistics if a metallic stent needs to be made radioactive. That is, by the time the stent is ready for use, its radioactivity level may have decayed to a point which makes it unsuitable for the intended purpose.
A discussion of the irradiation of nickel-titanium or steel is found in German patent P 4315002 issued to Christoff, and corresponding PCT application EP 94-01373 which corresponds to EP 94 916177.2, reporting on a metallic stent with a short and a long half-life.
While the prior art reports on various ways to make a metallic stent radioactive, for the purpose of practical use it is assumed that the availability of a non-radioactive metallic stent has considerable advantages. It is a principal aim of the present invention to provide a method to provide radioactivity without incorporating the radioactive material into a metallic stent or irradiating the stent itself. In this way, the radioactivity can be more easily integrated, manufactured, maintained, controlled, distributed, and so forth, than is possible with a radioactive metallic stent that is produced by the usual known methods.